Galectins are a family of galactose-binding proteins present in the cytoplasm with multiple biological activities. Galectin-3 is implicated in various cancers and galectin-1 increase HIV-1 attachment to target cells. The discovery of selective inhibitors of galectins could lead to new anti-cancer or antiviral agents. The purpose of our research is the synthesis of selective galectin inhibitors with unique pharmacokinetic properties. We propose that substituting the hydroxyl groups present on the galactopyranoside core will procure analogs with improved biological activities, superior metabolic stabilities and enhanced pharmacokinetic profile. The fluorinated carbohydrates represent a good strategy to improve protein-carbohydrate interactions via desolvation together with attractive dipolar interactions mediated by the polar C-F bonds. The incorporation of fluorine atoms in a pyranose sugar unit does not have a deleterious effect on the interactions with the binding site of the protein, despite the absence of any hydrogen bond donating capacity and the reduced aptitude to accept hydrogen bonds. A Chiron approach was used to access a library of fluorinated galactosides: all the monofluorogalactosides, a trifluorogalactoside and a tetrafluorogalactoside. All the derivatives were evaluated over galectin-1 and galectin-3 using quantitative enzyme-linked immunosorbent assay (ELISA) tests. The results show that some fluorinated galactopyranosides have selectivity toward galectin-1. The stereochemistry of the fluorine groups were confirmed using X-ray crystallography and NMR spectroscopy.

Synthesis and biological evaluations of mono- and poly-fluorogalactopyranosides: Preparation of selective galectin inhibitors

255th National Meeting (2018)

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